The invention relates to 2-alkyl-5-halogen-pent-4-enecarboxylic acid and its esters and salts in the form of its racemates and enantiomers and a process for the preparation of these carboxylic acids.
In the EP-A-0 678 503, xcex4-amino-xcex3-hydroxy-xcfx89-aryl-alkanecarboxamides are described, which exhibit renin-inhibiting properties and could be used as antihypertensive agents in pharmaceutical preparations. The manufacturing procedures described are unsatisfactory in terms of the number of process steps and yields and are not suitable for an industrial process. A disadvantage of these processes is also that the total yields of pure diastereomers that are obtainable are too small.
In a new process, one starts from 2,7-dialkyl-8-aryl-4-octenoyl amides, whose double bond is simultaneously halogenated in the 5-position and hydroxylated in the 4-position under lactonization, then the halogen is substituted by azide, the lactone amidated and the azide then transferred to the amine group. The desired alkanecarboxamides are obtained with the new process both in high total yields and in a high degree of purity, and selectively pure diastereomers can be prepared. The halolactonization of process step a), the azidation of process step b), and the azide reduction of process stop d) are described by P. Herold in the Journal of Organic Chemistry, Vol. 54 (1989), pages 1178-1185.
The 2,7-dialkyl-8-aryl-4-octenoyl amides may correspond for example to formula A, 
and especially to formula A1
wherein R1 and R2 independently of one another are H, C1-C6alkyl, C1-C6halogenalkyl, C1-C6alkoxy, C1-C6alkoxy-C1-C6alkyl, or C1-C6alkoxy-C1-C6alkyloxy, R3 is C1-C6alkyl, R4 is C1-C6alkyl, R6 is C1-C6alkyl, R5 is C1-C6alkyl or C1-C6alkoxy, or R5 and R6 together are tetramethylene, pentamethylene, 3-oxa-1,5-pentylene or xe2x80x94CH2CH2Oxe2x80x94C(O)xe2x80x94 substituted if necessary with C1-C4alkyl, phenyl or benzyl.
The compounds of formulae A and A1 are obtainable by reacting a compound of formula B 
as racemate or enantiomer, with a compound of formula C, as racemate or enantiomer, 
wherein R1 to R4, R5 and R6 are as defined above, Y is Cl, Br or I and Z is Cl, Br or I, in the presence of an alkali metal or alkaline earth metal. Y and Z are preferably Br and especially Cl.
It is expedient to prepare the compounds of formula C from the carboxylic acids corresponding to the amides, and their esters or acid halides, and these thus represent valuable intermediates for the preparation of the antihypertensive compositions mentioned previously. The formation of carboxamides from carboxylic acid esters and amines in the presence of trialkyl aluminium or dialkyl aluminium halide, for example using trimethyl aluminium or dimethyl aluminium chloride, is described by S. M. Weinreb in Org. Synthesis, VI, page 49 (1988).
A further object of the invention is represented by compounds of formula I in the form of racemates and enantiomers, 
wherein
R4 is C1-C6alkyl, Z is chlorine, bromine or iodine, and X is xe2x80x94OH, chloride, bromide or iodide, or X forms an ester group with the carbonyl substituent as well as salts of carboxylic acids.
Especially preferred enantiomers are those of formula Ia 
R4 is preferably C1-C4alkyl. Examples of alkyl are methyl, ethyl, n- and i-propyl, n-, i- and t-butyl, pentyl and hexyl. It is very particularly preferred when R4 is i-propyl.
It is especially preferred when Z is Cl.
In the ester group, X is preferably a substituent of formula R2Oxe2x80x94, where R7 is an organic group with 1 to 18, preferably 1 to 12, and especially preferably 1 to 8 C-atoms and it necessary comprises heteroatoms selected from group O and N.
R7 may be a branched and preferably linear alkyl, preferably comprising 1 to 4 C-atoms. Examples are methyl, ethyl, n-propyl, n-butyl, pentyl, hexyl, heptyl and octyl. Especially preferred are methyl and ethyl. The alkyl may be substituted, for example with C1-C4alkoxy, such as methoxy or ethoxy. Examples of substituted alkyl are methoxethyl and ethoxyethyl.
R7 may be cycloalkyl with 3 to 8, and preferably 5 or 6 ring-carbon atoms. Examples are cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. The cycloalkyl may be substituted with C1-C4alkyl or C1-C4alkoxy.
R7 may be cycloalkyl-C1-C4alkyl with 3 to 8, and preferably 5 or 6 ring-carbon atoms, which is unsubstituted or substituted with C1-C4alkyl or C1-C4alkoxy. Examples are cyclopentylmethyl, cyclohexylmethyl, methylcyclohexylmethyl and cyclohexylethyl.
R7 may be C6-C10aryl which is unsubstituted or substituted with C1-C4alkyl or C1-C4alkoxy. Examples are phenyl, naphthyl, methylphenyl, ethylphenyl and i-propylphenyl.
R7 may be C6-C10aryl-C1-C4alkyl which is unsubstituted or substituted with C1-C4alkyl or C1-C4alkoxy. Examples are benzyl, methylbenzyl and phenylethyl.
Of the acid halides of formula I, the chlorides and bromides are preferred.
The salts of carboxylic acids may for example be alkali metal or alkaline earth metal salts, as well as ammonium salt. Of the alkali metals and alkaline earth metals, lithium, sodium, potassium, magnesium and calcium are preferred. Suitable forms of ammonium are the ammonium cation, the cations of primary, secondary, and tertiary amines, and quaternary ammonium; these cations may comprise 1 to 20, preferably 1 to 16 C-atoms.
Especially preferred compounds of formulae I and Ia are those wherein Z is chlorine, R4 is C1-C4alkyl and especially preferably i-propyl, and X is OH, Cl, Br or C1-C4alkoxy.
A particularly preferred embodiment includes compounds of formulae I and Ia wherein Z is chlorine, R4 is i-propyl, and X is OH, Cl, Br, methoxy or ethoxy.
Especially preferred are compounds of formulae I and Ia wherein Z is chlorine, R4 is i-propyl, and X is Cl or ethoxy.
The compounds of formula I are obtainable for example by reacting isovaleric acid esters with 1,3-dihalogenpropene in the presence of strong amine bases, such as alkali metal amides (Li-N(i-propyl)2 or lithium hexamethyldisilazane) to form the esters of formula I, and preparing therefrom by derivatization in a manner known per se the carboxylic acids, carboxylic acid halides and carboxylic acid salts. The desired enantiomers can be obtained from the racemates in a manner known per se by separating the racemates, for example by crystallization from addition salts of carboxylic acids using optically active bases. It is more advantageous to separate the racemates by treating esters of formula I with esterases.
A further object of the invention is a process for the preparation of compounds of formula I comprising the reaction of a compound of formula II, 
wherein Z and Zxe2x80x3 are independently of one another chlorine, bromine or iodine, and preferably chlorine or bromine, in the presence of strong amine bases with a compound of formula III, 
wherein X forms an ester group with the carbonyl substituent and R4 is C1-C6alkyl, and if necessary derivatization of the resulting carboxylic acid esters of formula I to form carboxylic acids, carboxylic acid halides or carboxylic acid salts.
The strong amine bases are preferably alkali metal amides. It is expedient to carry out the reaction using ether as solvent and cooling to approximately ambient temperature. Cooling can mean down to about xe2x88x9220xc2x0 C.
The compounds of formula Ia can also be obtained by asymmetric synthesis.
A further object of the invention is a process for the preparation of compounds of formula Ia comprising the reaction of a compound of formula IV, 
with a carboxylic acid halide of formula R4CH2xe2x80x94COxe2x80x94X, wherein R4 is as defined above and X is chlorine, bromine or iodine, and reaction of the resulting compound of formula V, 
first with lithium hexamethyldisilazide and then with a compound of formula II, 
wherein Z and Zxe2x80x3 are independently of one another chlorine, bromine or iodine, followed by hydrolyzation of the resulting compound of formula VI 
with a base which isolates the salts or carboxylic acids of formula Ia, and if necessary derivatization of the carboxylic acids to form esters or halogenides.
An alkali metal base, for example LiOH, NaOH or KOH, is preferably used as the base, to accelerate the hydrolysis, an oxidizing agent may also be used, such as hydrogen peroxide. The individual process steps are analogous to processes that are known to a person skilled in the art and are described in more detail in the following examples.